Heterocyclic compounds and their preparation and use

ABSTRACT

The present invention relates to therapeutically active azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer&#39;s disease, severe painful conditions and glaucoma.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of Ser. No. 07/744,160 filed Aug. 13, 1991, now U.S. Pat. No. 5,260,314.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to therapeutically active azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds.

The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.

2. Description of Related Art

Due to the in general improved health situation in the western world, elderly-related diseases are much more common now than in the past and are likely to be even more common in the future.

One of the elderly-related symptoms is a reduction of the cognitive functions. This symptom is especially pronounced in the pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also most likely caused by, a up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as of hippocampus, namely learning, association, consolidation and recognition.

It is a characteristic of Alzheimer's disease that although the cholinergic neurons degenerate, then the postsynaptic muscarinic receptors in the forebrain and hippocampus still exist. Therefore muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease and in improving the cognitive functions of elderly people.

It is well known that arecoline (methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergic agonist.

Arecoline however has a very short biological half life and a small separation between central and peripheral muscarinic effects. Furthermore arecoline is a rather toxic compound.

EP-A-0307142 discloses a class of thiadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity, or a hydrocarbon substituent, which are muscarinic agonists and therefore useful in the treatment of neurological and mental illnesses and severe painful conditions.

It is an object of the invention to provide new muscarinic cholinergic compounds.

SUMMARY OF THE INVENTION

The novel compounds of the invention are heterocyclic compounds having the formula I ##STR1## wherein X is oxygen or sulphur;

R is halogen, --CHO, --NO₂, --OR⁴, --SR⁴, --SOR⁴ and --SO₂ R⁴, wherein R⁴ is straight or branched C₁₋₁₅ -alkyl, straight or branched C₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅ -alkynyl, optionally substituted with one or more halogen(s), --CF₃, --CN, phenyl or phenoxy wherein the phenyl or phenoxy group may be optionally substituted with halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy, or a phenyl or benzyloxycarbonyl group each of which may be optionally substituted with halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy, or --OR⁵ Y, --SR⁵ Y, --OR⁵ ZY, --SR⁵ ZY, wherein Z is oxygen or sulphur, R⁵ is straight or branched C₁₋₁₅ -alkyl, straight or branched C₂₋₁₅ -alkenyl, straight or branched C₂₋₁₅ -alkynyl, and Y Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at a carbon or nitrogen atom with straight or branched C₁₋₆ -alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group; and

G is selected from one of the following azabicyclic rings ##STR2## wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R¹ and R² may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C₁₋₅ -alkyl, straight or branched ₂₋₅ -alkenyl, straight or branched C₂₋₅ -alkenyl, straight or branched C₁₋₁₀ -alkoxy, straight or branched C₁₋₅ -alkyl substituted with --OH, --OH, halogen, --NH₂ or carboxy; R³ is H, straight or branched C₁₋₅ -alkyl, straight or branched C₂₋₅ -alkenyl or straight or branched C₂₋₅ -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2; and is a single or double bond; or a pharmaceutically acceptable salt thereof.

Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salt.

The compounds of this invention are also useful analgesic agents and therefore useful in the treatment of severe painful conditions.

Furthermore, the compounds of this invention are useful in the treatment of glaucoma.

The invention also relates to methods of preparing the above mentioned compounds, comprising:

a) reacting a compound of formula II ##STR3## wherein G has the meaning defined above, > N is >--NH or >═N and R⁶ is H, OH or O-alkyl, with S₂ Cl₂ to form a compound of formula III ##STR4## wherein G has the meaning defined above; subsequent displacement of Cl with an appropriate nucleophile gives a compound of formula I wherein X is S, or

b) dehydrating a compound of formula IV ##STR5## wherein G has the meaning defined above and R⁷ is alkyl, amino, halogen, alkoxy or alkylthio, to form a compound of formula V ##STR6## wherein G and R⁷ have the meanings defined above, or c) when R⁷ in formula V is amino, the amino group can be substituted by chloro by known procedures, and subsequent displacement of Cl with an appropriate nucleophile gives a compound of formula I wherein X is O, or

d) oxidizing a compound of formula VI ##STR7## wherein G, R⁴ and X have the meanings defined above by standard procedures to form a compound of formula VII ##STR8## and subsequent displacement of --SO₂ --R⁴ with an appropriate nucleophile to form a compound of formula I.

It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of formula I as well as the racemates.

The pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of ³ H-Oxotremorine-M (³ H-Oxo). Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V. (1980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain". Proc. Roy. Soc. London (Series B) 207,1.

³ H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors). Three different sites are labelled by ³ H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.

The inhibitory effects of compounds on ³ H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.

All preparations are performed at 0°-4° C. unless otherwise indicated. Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 s in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined suspension centrifuged for 15 min at 40,000×g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2×10 ml of buffer and centrifuged for 10 min at 40,000×g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 μl of test solution and 25 μl of ³ H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min at 25° C. Non-specific binding is determined in triplicate using arecoline (1 μg/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibre filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.

Test substances are dissolved in 10 ml water (if necessary heated on a steam bath for less than 5 minutes) at a concentration of 2.2 mg/ml. 25-75% inhibition of specific binding must be obtained before calculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration (ng/ml) of the test substance which inhibits the specific binding of ³ H-Oxo by 50%). ##EQU1## where C_(o) is specific binding in control assays and C_(x) is the specific binding in the test assay. (The calculations assume normal mass-action kinetics).

Test results obtained by testing some compounds of the present invention will appear from the following table 1.

                  TABLE 1                                                          ______________________________________                                                        Inhibition in vitro                                                            OXO BINDING                                                     Compound No.   (ng/ml)                                                         ______________________________________                                          1             156                                                              2             270                                                              3             208                                                              4             21                                                               5             18                                                               6             >300                                                             7             13                                                               8             5.2                                                              9             0.69                                                            10             1.7                                                             11             1.2                                                             12             0.45                                                            13             0.65                                                            14             4.8                                                             15             0.61                                                            16             67                                                              17             3.2                                                             18             7.5                                                             20             11                                                              21             0.96                                                            22             3.4                                                             23             43                                                              24             0.52                                                            25             1.9                                                             26             1.4                                                             27             17                                                              28             1.9                                                             29             0.39                                                            30             0.13                                                            31             0.6                                                             32             0.45                                                            33             6.4                                                             34             7.9                                                             35             1.9                                                             36             0.82                                                            37             2.0                                                             39             0.52                                                            40             0.19                                                            41             0.56                                                            42             0.35                                                            43             2.33                                                            44             4.7                                                             45             1.6                                                             46             0.56                                                            47             >300                                                            48             0.43                                                            49             0.33                                                            50             1.0                                                             51             0.89                                                            52             0.61                                                            53             0.3                                                             54             3.1                                                             55             0.43                                                            56             0.14                                                            57             4.6                                                             62             1.9                                                             63             8.2                                                             64             8.2                                                             65             9.6                                                             67             0.43                                                            68             0.69                                                            74             0.45                                                            75             0.96                                                            76             2.6                                                             77             0.89                                                            78             0.30                                                            79             0.50                                                            80             0.30                                                            81             0.40                                                            82             0.40                                                            83             0.43                                                            84             13                                                              85             7.2                                                             86             3.5                                                             87             10                                                              88             6.1                                                             89             12                                                              90             3.3                                                             91             5.2                                                             92             1.5                                                             93             9.0                                                             94             12                                                              95             1.7                                                             96             0.3                                                             98             1.0                                                             100            0.82                                                            101            0.75                                                            102            1.52                                                            103            0.92                                                            104            0.85                                                            106            0.9                                                             107            0.3                                                             108            16                                                              109            4.0                                                             110            1.1                                                             111            0.32                                                            112            0.19                                                            113            0.26                                                            114            0.15                                                            115            0.50                                                            116            1.4                                                             117            2.0                                                             118            0.35                                                            119            0.30                                                            120            0.28                                                            121            0.32                                                            122            0.67                                                            123            0.47                                                            130            0.60                                                            131            0.96                                                            132            0.96                                                            133            0.45                                                            134            0.47                                                            ______________________________________                                    

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective muscarinic cholinergic agonistic amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of the active ingredient or, more broadly, one (1) to hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl cellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Ampoules are convenient unit dosage forms. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application. A syrup, elixir of the like can be used in cases where a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit form comprising 1-100 mg in a pharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-100 mg/day, preferably 10-70 mg/day, when administered to patients, e.g. humans, as a drug.

A typical tablet which may be prepared by conventional tabletting techniques contains:

    ______________________________________                                         Active compound     5.0    mg                                                  Lactosum            67.8   mg Ph.Eur.                                          Avicel ®        31.4   mg                                                  Amberlite ®     1.0    mg                                                  Magnesii stearas    0.25   mg Ph.Eur.                                          ______________________________________                                    

Due to the high muscarinic cholinergic receptor agonistic activity, the compounds of the invention are extremely useful in the treatment symptoms related to a reduction of the cognitive functions of the brain of mammals, when administered in an amount effective for stimulating the cognitive functions of the forebrain and hippocampus. The important stimulating activity of the compounds of the invention includes both activity against the pathophysiological disease, Alzheimer's disease as well as against normal degeneration of brain function. The compounds of the invention may accordingly be administered to a subject, e.g., a living animal body, including a human, in need of stimulation of the cognitive functions of the forebrain and hippocampus, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective forebrain and hippocampus stimulating amount, and in any event an amount which is effective for improving the cognitive function of mammals due to their muscarinic cholinergic receptor agonistic activity. Suitable dosage ranges are 1-100 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge. 

